Constitutive OGG1 variant together with BRCA mutations display accelerated telomere shortening

Dissertação de mestrado, Oncobiologia, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2015

Osorio, Milne et al. (2014) reported a SNP, rs2304277, in the OGG1 gene, with evidence of potential association with increased ovarian cancer risk in BRCA1 germline mutation carriers (p=4.8x10-3). The protein OGG1 is a main player in the DNA BER pathway, responsible for recognizing and excising oxidized guanines (8-oxoG). In the literature, oxidative stress has been well characterized to have a natural site-specific preference for guanines, in which telomeric DNA is enriched due to several TTAGGG repeats. 8-oxoG is highly mutagenic and affects DNA replication, and at the telomere level it can impair the recruitment and affinity of the shelterin complex proteins. This complex caps and protects telomeres from aberrant chromosomal rearrangements. Not only, when not properly corrected, 8-oxoG can give rise to ssDNA breaks. Therefore, telomeres are more susceptible to this kind of damage, and disruption of the normal telomere function and length can result in carcinogenesis, as a consequence of genomic instability. Hence, given the role of OGG1 and telomeres composition, we aimed to explore whether the increase of cancer risk in the carriers of rs2304277 (together with a germline mutation in the BRCA gene), might be due to an altered OGG1 function, which could accelerate the telomere shortening, resulting from a weaker response upon oxidative stress harms. For the functional characterization of the polymorphism, the experimental approach was based on the evaluation of the OGG1 mRNA expression levels by qPCR and measurement of telomeres length by High Throughput Q-FISH of the different OGG1 genotypes and BRCA1/2 mutation status from peripheral blood samples. Very preliminary results, suggest that the variant leads to a decrease in OGG1 mRNA levels which, and together with a mutation in BRCA gene might contribute to an accelerated telomere shortening. These results might explain, in part, the increase of an individual’s lifetime risk of developing cancer when harbouring both genetic conditions.